Sexual dimorphic cell type and connectivity atlases of the aging and AD mouse brains

衰老和 AD 小鼠大脑的性二态性细胞类型和连接图谱

• 批准号: 10740308
• 负责人: Hong-Wei Dong
• 金额: $ 145.07万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740308
• 关键词: 3-Dimensional; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid; Anatomy; Androgen Receptor; Atlases; BRAIN initiative; Brain; Catalogs; Communities; Data; Data Set; Deterioration; Diffusion Magnetic Resonance Imaging; Disease Progression; Dorsal; ESR1 gene; Early Onset Alzheimer Disease; Elderly; Etiology; Female; Genetic; Glutamates; Hippocampus; Image; Impaired cognition; Informatics; Interneurons; Label; Late Onset Alzheimer Disease; Light; Manuals; Maps; Methods; Microscopy; Molecular; Morphology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurosciences Research; Online Systems; Pathogenesis; Pathologic; Pathology; Process; Regional Anatomy; Research; Resolution; Rodent; Senile Plaques; Sex Differences; Sex Differentiation; Stains; Synapses; Synaptophysin; Technology; Tracer; Transgenic Mice; Translating; Visualization; Work; aging brain; aging hippocampus; cell type; data portal; data visualization; experience; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; male; molecular domain; mouse model; multimodality; neural circuit; normal aging; prevent; reconstruction; resilience; response; sex; sexual dimorphism; superresolution imaging; tau Proteins; tool; transmission process; virtual reality

Project Abstract In response to NOT-21-039 and related PAR-22-093, we propose this project to address several urgent needs in the field. Mouse models spanning different ages and sexes are routinely used to quantify anatomic, molecular, and pathologic changes in neurodegenerative diseases like Alzheimer’s Disease (AD). Yet, the only available standard mouse brain atlases are constructed from 2-month-old adult male mice. Furthermore, although both normal aging and AD neurodegeneration display sexually dimorphic features, the scientific community lacks the sexually differentiated rodent brain atlases necessary to study these attributes. By applying cutting edge technologies, we have developed for BRAIN Initiative connectomic and cell type mapping projects, we will (1) generate sexually dimorphic 3D aging and AD brain atlases with granular hippocampus (HPF) molecular domains, that can be used as standard atlas templates for all HPF work and (2) we will comprehensively characterize morphological dystrophies, as well as connectional and synaptic disruptions, in aging and AD. In Specific Aim 1, publicly available standard 3D HPF atlases of aging and AD brains will be created. Data will be generated in 2-, 9-, and 18-month-old wildtype (WT), 5xFAD (early AD onset), and MAPT(H1)*N279K (late AD onset) male and female mice. Fine HPF domain delineations will be facilitated by 3D volumetric images of cyto- and myeloarchitecture, while additional histopathological markers (Aβ plaques/tau tangles) and chemoarchitectural details (glutamate, GABA, PV, SST, Calb1) will be mapped to create comprehensive histopathological and chemoarchitectural HPF atlases. In Specific Aim 2, We will systematically apply a genetic MORF3 sparse labeling approach to label, reconstruct, and analyze cell type specific neuronal morphology of all HPF regions at the granular level of their domains in WT, Vglut1.MORF3/5xFAD, PV.MORF3/5xFAD, Vglut1.MORF3/MAPT(H1)*N279K, and PV.MORF3/MAPT(H1)*N279K mice across age and sex. Our whole brain 3D clearing, immunostaining, imaging, and 3D neuronal reconstruction pipeline will be applied. Given that an etiology of AD-related cognitive decline is selective HPF synaptic disruptions, with dorsal HPF nodes being some of the earliest affected in AD, in Specific Aim 3, will examine progressive connectional disruptions along amyloid and tau pathology progression. Male and female MORF3 and double transgenic mice, MORF3/5xFAD and MORF3/MAPT(H1)*N279K, at 2m, 9m, and 18m of age will be used to reveal potential connectivity changes across aging and AD. The same groups will be used to determine synaptic-level HPF disruptions with the application of Expansion Microscopy that will capture super-resolution images of synaptic connections. In Specific Aim 4, we will create a web-based data portal that enables visualization, comparison, and analysis of neural circuits and cell types in 3D aging and AD brains. Our team, with decades of experience in connectomics, brain atlasing, and online visualization, is sure to deliver standard HPF atlas templates for all neuroscience research and to determine sexually dimorphic anatomic regions vulnerable across age and AD progression.

项目摘要 为了响应 NOT-21-039 和相关的 PAR-22-093，我们提出这个项目来解决几个紧急需求 在该领域，不同年龄和性别的小鼠模型通常用于量化解剖学、分子学、 以及阿尔茨海默病 (AD) 等神经退行性疾病的病理变化。 标准小鼠脑图谱是由 2 个月大的成年雄性小鼠构建的。 正常衰老和 AD 神经变性表现出性别二态性特征，科学界缺乏 通过应用尖端技术，研究这些属性所需的性别分化的啮齿动物大脑图谱。 技术，我们为 BRAIN Initiative 连接组和细胞类型绘图项目开发，我们将 (1) 使用颗粒海马 (HPF) 分子生成性别二态性 3D 衰老和 AD 脑图谱 域，可以用作所有 HPF 工作的标准图集模板，并且 (2) 我们将全面 表征衰老和 AD 中的形态营养不良以及连接和突触破坏。 具体目标 1，将创建公开的衰老和 AD 大脑的标准 3D HPF 图集。 在 2、9 和 18 个月大的野生型 (WT)、5xFAD（AD 早期发病）和 MAPT(H1)*N279K（AD 晚期）中生成 细胞的 3D 体积图像将有助于对雄性和雌性小鼠进行精细的 HPF 域描绘。 和骨髓结构，同时附加组织病理学标记（Aβ 斑块/tau 缠结）和 化学结构细节（谷氨酸、GABA、PV、SST、Calb1）将被映射以创建全面的 在具体目标 2 中，我们将系统地应用遗传学的组织病理学和化学结构 HPF 图谱。 MORF3 稀疏标记方法可标记、重建和分析所有细胞类型特定的神经元形态 HPF 区域位于 WT、Vglut1.MORF3/5xFAD、PV.MORF3/5xFAD、 不同年龄和性别的 Vglut1.MORF3/MAPT(H1)*N279K 和 PV.MORF3/MAPT(H1)*N279K 小鼠。 鉴于此，将应用大脑 3D 透明化、免疫染色、成像和 3D 神经重建流程。 AD 相关认知能力下降的病因是选择性 HPF 突触破坏，其中背侧 HPF 节点 在具体目标 3 中，一些最早受影响的 AD 将检查渐进性连接中断 淀粉样蛋白和 tau 蛋白病理学进展。雄性和雌性 MORF3 和双转基因小鼠，MORF3/5xFAD。 和 MORF3/MAPT(H1)*N279K，在 2m、9m 和 18m 时将用于揭示潜在的连接变化 相同的组将用于确定突触水平 HPF 破坏。 扩展显微镜的应用将捕获突触连接的超分辨率图像。 具体目标 4，我们将创建一个基于 Web 的数据门户，实现可视化、比较和分析 3D 衰老和 AD 大脑中的神经回路和细胞类型 我们的团队在连接组学方面拥有数十年的经验， 大脑图谱和在线可视化肯定会为所有神经科学提供标准的 HPF 图谱模板 研究并确定在年龄和 AD 进展过程中易受影响的性别二态性解剖区域。